TR&D 3 Project Summary The primary goal of TR&D 3 is to develop PET radiopharmaceuticals to enable molecular imaging of interplay between inflammation and oxidative stress. Of note, oxidative stress represents an imbalance between production of reactive oxygen species (ROS) and their elimination or mitigation by antioxidants. Excess ROS is in the pathogenesis of a wide range of diseases. Importantly, a key mediator of oxidative stress is nitric oxide (NO) which is generated by the nitric oxide synthase (NOS) family of enzymes. Among this NOS family, the inducible form of NO has been implicated in a variety of diseases, wherein either acute or chronic inflammation is central to disease pathogenesis. Moreover, excess NO can react with free radicals to generate reactive nitrogen species (RNS) such as peroxynitrites, thus impairing cell function. In view of the high significance of abovementioned molecular targets in the pathogenesis of disease, the specific aims of TR&D 3 are to design, synthesize, and validate: 1) radiotracers targeting inducible nitric oxide synthase (iNOS); and 2) gallium-68 incorporated PET tracers for imaging ROS/RNS-mediated oxidative stress. Radiotracers developed in TR&D 3 will be initially validated in animal models at our institution. Following validations of target-sensitivity and ?specificity of new PET tracers at a molecular level in vivo using proposed methodologies, TR&D 3 will collaborate with CPs to validate and further optimize the technology for wide utility in disease-specific applications. Overall, these PET tracers will provide novel imaging resource to interrogate role of these vital biomarkers in inflammation. involved